The reciprocal expansion of Th1 and Th2 subsets is now recognized as a central feature of the immunopathogenesis of several human and experimental diseases. Infection of inbred strains of mice with Leishmania major is the model system for studying the in vivo regulation of protective and non-protective CD4+ subsets and a paradigm for disease that have a genetic basis for susceptibility. Dr Reiner is uniquely positioned to dissect the exact mechanism(s) responsible for the Th1 and Th2 switch in a well- characterized infectious disease model. To facilitate this, he has spent the past year developing an assay that provides a precise method for analysis of in vivo cytokine regulation and successfully generating transgenic mice that express a T cell receptor recognizing a dominant leishmanial epitope. There are three specific aims proposed: 1. To characterize the early immune response to murine leishmaniasis by in vivo analysis of gene expression for various cytokines and effector molecules. 2. To determining the necessary and sufficient conditions governing the preferential expansion of a Th1 and Th2 response to experimental leishmaniasis by in vivo administration and neutralization of critically implicated cytokines in TcR-transgenic mice. 3. To identify the mechanism(s) of genetic susceptibility by in vitro modeling using antigen-presenting and accessory cell populations from resistant and susceptible mice plus transgenic Leishmania-specific T cells.